Investigating the impact of lactate on the macrophage response in tuberculosis disease.

Tuberculosis (TB) is a pathogen infecting macrophages in the lung where it can persist for decades. It is a global public health challenge; in 2021, 10.6 million people fell ill with TB and 1.6 million died1, despite vaccination and available treatments. The emergence of multidrug resistant TB and new antibiotic resistance strains exacerbate disease burden. Macrophages

are capable of bactericidal activity towards Mycobacterium tuberculosis (M.tb), essential for infection control. To design novel host-directed therapies, a better understanding of how M.tb infection impacts host immune responses is crucial. Lungs of M.tb-infected hosts are lactate-rich environments. We were among the first to show

that lactate is an active signalling molecule and that macrophages respond to it through different transporters and receptors with the activation of pro- or anti-inflammatory responses, depending on the context. We have a poor understanding of how lactate shapes macrophage responses to M.tb and how this dictates infection outcome. The current

hypothesis is that lactate in TB lungs promotes macrophage M.tb killing. To this end we need to investigate the impact of lactate on macrophage function and M.tb infection resolution. Exploiting this knowledge could be key for the design of new TB therapies, which are an urgent, unmet need.